Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an impurity in an illicit drug, is expressed after its oxidation to 1-methyl-4-phenylpyridinium by monoamine oxidase. The pyridinium is concentrated by carrier-mediated transport into the mitochondria where it inhibits NADH dehydrogenase and, hence, ATP synthesis. Some structurally related compounds have been tested for their effect on the oxidation of NAD+-linked substrates in intact mitochondria, and for the inhibition of the accumulation of the pyridinium into mitochondria and of NADH dehydrogenase activity in a membrane preparation. Some pyridine derivatives are more inhibitory to NADH dehydrogenase than is 1-methyl-4-phenylpyridinium but these are not concentrated into mitochondria by the uptake system. 4-Phenylpyridine, one of the most effective inhibitors, both occurs naturally and is an environmental pollutant.
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PMID:Inhibition of NADH oxidation by pyridine derivatives. 288 24

The kinetics of ATP synthesis by bovine heart submitochondrial particles (SMP) are modulated by the rate of energy production by the respiratory chain between two fixed limits characterized by apparent KmADP = 2-4 microM and Vmax approximately 200 nmol of ATP min-1 (mg of SMP protein)-1 at low energy levels and apparent KmADP = 120-160 microM and Vmax = 11,000 nmol of ATP min-1 (mg of SMP protein)-1 at high energy levels. These data indicate that KmADP and Vmax increase approximately 50-fold each; therefore, there is essentially no change in the catalytic efficiency of the ATP synthase complex in going from one extreme to the other. At intermediate rates of energy production, the kinetic data required introduction of a third, intermediate KmADP. A KmADP of 10-15 microM fitted all the data reported here and previously [Matsuno-Yagi, A., & Hatefi, Y. (1986) J. Biol. Chem. 261, 14031-14038]. However, this is not meant to suggest that there is a fixed intermediate KmADP, as the transition from one fixed limit to the other may be fluid or involve more than one intermediate state. In addition, it has been shown that kinetic plots of SMP-catalyzed and ATP-driven reverse electron transfer from succinate to NAD are curvilinear and resolvable into a minimum of two apparent KmNAD values of about 20-30 and 200-300 microM. These results have been discussed in relation to the three potentially active catalytic sites of F1-ATPase and the structure of the NADH:ubiquinone oxidoreductase complex, the curvilinear kinetics of ATP hydrolysis, and changes in KmADP and KmPi in photophosphorylation as affected by the duration and intensity of light.
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PMID:Energy-induced modulation of the kinetics of oxidative phosphorylation and reverse electron transfer. 290 68

The mechanism of coupling between mitochondrial ATPase (EC 3.6.1.3) and nicotinamide nucleotide transhydrogenase (EC 1.6.1.1) was studied in reconstituted liposomes containing both purified enzymes and compared with their behavior in submitochondrial particles. In order to investigate the mode of coupling between the transhydrogenase and the ATPase by the double-inhibitor and inhibitor-uncoupler methods, suitable inhibitors of transhydrogenase and ATPase were selected. Phenylarsine oxide and A3'-O-(3-(N-(4-azido-2-nitrophenyl)amino)propionyl)-NAD+ were used as transhydrogenase inhibitors, whereas of the various ATPase inhibitors tested aurovertin was found to be the most convenient. The inhibition of the ATP-driven transhydrogenase activity was proportional to the inhibition of both the ATPase and the transhydrogenase. Inhibitor-uncoupler titrations showed an increased sensitivity of the coupled reaction towards carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)--an uncoupler that preferentially uncouples localized interactions, according to Herweijer et al. (Biochim. Biophys. Acta 849 (1986) 276-287)--when the primary pump was partially inhibited. However, when the secondary pump was partially inhibited the sensitivity towards FCCP remained unchanged. Similar results were obtained with submitochondrial particles. These results are in contrast to those obtained previously with the ATP-driven reverse electron flow. In addition, the amount of uncoupler required for uncoupling of the ATP-driven transhydrogenase was found to be similar to that required for the stimulation of the ATPase activity, both in reconstituted vesicles and in submitochondrial particles. Uncoupling of reversed electron flow to NAD+ required much less uncoupler. On the basis of these results, it is proposed that, in agreement with the chemiosmotic model, the interaction between ATPase and transhydrogenase in reconstituted vesicles as well as in submitochondrial particles occurs through the delta mu H+. In contrast, the energy transfer between ATPase and NADH-ubiquinone oxidoreductase appears to occur via a more direct interaction, according to the above-mentioned results by Herweijer et al.
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PMID:ATP-driven transhydrogenase provides an example of delocalized chemiosmotic coupling in reconstituted vesicles and in submitochondrial particles. 296 Mar 79

Some aspects of the interaction of the extrinsic, potential-sensitive, molecular probe diS-C3-(5) with pigeon heart mitochondria are reported in this paper. Binding studies based on fluorimetry indicate that the ratio of the dissociation constant to the maximum number of binding sites, KD/n, is larger for succinate-containing mitochondria than that for cyanide-inhibited preparations. These observations suggest that the basis of the energy-dependent diS-C3-(5) optical signals is the ejection of the probe from the mitochondrial membrane. A more detailed analysis indicated that the major change in the binding parameters is a reduction in the maximum number of binding sites, n, when a charge gradient is formed at the expense of substrate. Using rapid mixing techniques, the time course of the passive association of diS-C3-(5) with mitochondria, that of the glutamate- and ATP-dependent optical signals, and the effect of this probe on the rate at which the energy-dependent cytochrome c oxidase Soret band shift signal develops have been monitored. Retardation the ATP-dependent cytochrome c oxidase Soret band shift signal suggests that the probe readily permeates the mitochondrial membrane. The first-order rate law that the glutamate-dependent signal obeys suggests that the rate-limiting step in the development of this signal is the dissociation of the dye from the mitochondrial membrane or the permeation of this membrane by the probe. The faster phase of the ATP-induced signal likely reflects the initial transfer of dye from the bulk aqueous phase followed by a slower probe permeation process that obeys a first-order rate law. This probe appears to distribute across the mitochondrial membrane in accordance with the transmembrane potential as judged by its effect on the ATP-dependent cytochrome c oxidase Soret band shift signal. DiS-C3-(5) also appears to inhibit the NADH dehydrogenase.
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PMID:Interaction of the extrinsic potential-sensitive molecular probe diS-C3-(5) with pigeon heart mitochondria under equilibrium and time-resolved conditions. 300 42

We investigated mechanisms of mitochondrial phototoxicity caused by the cationic cyanine dye N,N'-bis(2-ethyl-1,3-dioxylene)kryptocyanine (EDKC), examining the role of the mitochondrial membrane potential on the dye uptake by carcinoma cells in vitro, and both the dark and photosensitizing effects of the dye on the function of isolated mouse liver mitochondria. When human bladder carcinoma cells (EJ) were pretreated with 2,4-dinitrophenol or nigericin, cellular uptake of EDKC decreased or increased, respectively, consistent with dye uptake that is dependent on membrane potentials. In isolated liver mitochondria, during NADH linked substrate oxidation (using glutamate plus malate or beta-hydroxybutyrate as substrates), low concentrations of the dye (0.25-0.5 microM) sensitized mitochondria to illumination with long wavelength light and inhibited both basal and ADP-stimulated respiration. Similar effects were observed during succinate oxidation, but only at higher concentrations of EDKC (greater than 5 microM) and at 10-fold greater light doses. NADH coenzyme Q reductase (Complex I) activity was inhibited by dye with or without light to an extent comparable to the inhibition of glutamate plus malate oxidation. Activity of cytochrome c oxidase, the terminal enzyme in the electron transport chain, was photosensitized with high dye doses (greater than 5 microM) and light, but the extent of inhibition was much less than the inhibition of respiration with succinate as substrate. ATP synthetase (F0F1 ATPase) activity was minimally affected by 4.0 microM EDKC with or without 24 J/cm2 light. We conclude that at low concentrations of dye, respiratory Complex I is a primary target for EDKC dark and light-induced toxicities. If Complex I is bypassed by using succinate as a respiratory substrate, the mitochondria can tolerate much higher dye concentrations and light doses.
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PMID:Mechanisms of mitochondrial photosensitization by the cationic dye, N,N-bis(2-ethyl-1,3-dioxylene)kryptocyanine (EDKC): preferential inactivation of complex I in the electron transport chain. 311 97

This is the first report on in vivo effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrial respiration in mouse brain. C57/BL mice, injected with 40 mg/kg of MPTP subcutaneously, were sacrificed by cervical dislocation 5-6 h after the injection. Mitochondrial suspensions were prepared from whole brains. Mitochondrial respiration was studied polarographically. The state 3 respiration, i.e., the active respiration in the presence of tricarboxylic acid (TCA) cycle substrates and ADP with coupled phosphorylation of ADP to ATP, was significantly inhibited in mice treated with MPTP. This inhibition was prevented by pretreatment of mice with pargyline. Activity of mitochondrial NADH-ubiquinone oxidoreductase was also inhibited in mice treated with MPTP.
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PMID:Inhibition of mitochondrial respiration by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse brain in vivo. 314 46

The cell membrane of Mycoplasma mobile was isolated by either ultrasonic or French press treatment of intact cells. The membrane fraction contained all of the cellular lipids, but only one-third of cellular proteins and had a density of 1.14 g ml-1. The soluble fraction contained the NADH dehydrogenase activity of the cells, as well as a protein with an apparent molecular mass of 55 kDa that was phosphorylated in the presence of ATP. Lipid analyses of M. mobile membranes revealed that membrane lipid could be labelled by radioactive glycerol, oleate and to a much higher extent by palmitate but not by acetic acid. The membrane lipid fraction was composed of 54% neutral and 46% polar lipid. The major constituents of the neutral lipid fraction were free fatty acid, free cholesterol and cholesterol esters (45, 25 and 20%, respectively, of total neutral lipid fraction). The free cholesterol count was 13% (w/w) of total membrane lipids with a cholesterol:phospholipid molar ratio of about 0.9. Among the polar lipids, both phospho- and glycolipids were detected. The phospholipid fraction consisted of a major de novo-synthesized phosphatidylglycerol (approximately 63% of total phospholipids), plus exogenous phosphatidylcholine and sphingomyelin incorporated in an unchanged form from the growth medium. The glycolipid fraction was dominated by a single glycolipid (approximately 90% of total glycolipids) that was preferentially labelled by palmitic acid and showed a very high saturated:unsaturated fatty acids ratio.
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PMID:Characterization of membrane components of the flask-shaped mycoplasma Mycoplasma mobile. 325 10

It is widely believed that the nigrostriatal toxicity of MPTP is due to its oxidation by brain monoamine oxidase first to MPDP+, and eventually to MPP+. Following uptake by the synaptic dopamine reuptake system, it is concentrated in the matrix of striatal mitochondria by an energy-dependent carrier, energized by the electrical gradient of the membrane. At the very high intramitochondrial concentrations thus reached, MPP+ combines with NADH dehydrogenase at a point distal to its iron-sulfur clusters but prior to the Q10 combining site. This leads to cessation of oxidative phosphorylation, ATP depletion, and cell death. Other pyridine derivatives act similarly on NADH dehydrogenase but they are not acutely toxic unless concentrated by the MPP+ carrier.
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PMID:Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 328 90

Hepatocyte cytotoxicity caused by substituted benzoquinones was associated with increased cytosolic Ca2+ concentration. p-Benzoquinone-induced hepatotoxicity was enhanced when the hepatocytes were loaded with Ca2+ by preincubation with ATP. A similar order of potency of the substituted benzoquinones in releasing Ca2+ from isolated mitochondria and inducing hepatocyte cytotoxicity was found; in decreasing order, this was 2-Br-, unsubstituted-, 2-CH3-, 2,6-(CH3O)2-, 2,6-(CH3)2-, 2,5-(CH3)2-, 2,3,5-(CH3)3-, and 2,3,5,6-(CH3)4-benzoquinones (duroquinone). The cellular products of quinone metabolism, hydroquinones and glutathione conjugates, did not cause mitochondrial Ca2+ release. Benzoquinone-induced mitochondrial Ca2+ release was preceded by GSH conjugate formation and NAD(P)H oxidation but followed by mitochondrial swelling. With duroquinone, a slow GSH and NADPH oxidation preceded Ca2+ release, but GSH oxidation did not occur with Se-deficient mitochondria lacking glutathione peroxidase activity. Cyanide-insensitive respiration was also observed with duroquinone but not with benzoquinone, suggesting that duroquinone undergoes redox cycling. GSH was depleted by both arylation and oxidation with 2,6-(CH3O)2-, 2,6-(CH3)2-, 2,5(CH3)2-, and 2,3,5-(CH3)3-benzoquinones. Benzoquinone concentrations that totally depleted GSH did not cause Ca2+ release until intramitochondrial NAD(P)H was oxidized. Ca2+ release was also prevented when NAD(P)H generation was stimulated by the presence of isocitrate or 3-hydroxybutyrate. This suggests that mitochondrial Ca2+ release is associated with NAD(P)H oxidation catalyzed by NADH dehydrogenase with benzoquinone or by the glutathione peroxidase-glutathione reductase system with duroquinone.
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PMID:Quinone toxicity in hepatocytes: studies on mitochondrial Ca2+ release induced by benzoquinone derivatives. 342 29

In the present study we have used beef heart submitochondrial preparations (BH-SMP) to demonstrate that a component of mitochondrial Complex I, probably the NADH dehydrogenase flavin, is the mitochondrial site of anthracycline reduction. During forward electron transport, the anthracyclines doxorubicin (Adriamycin) and daunorubicin acted as one-electron acceptors for BH-SMP (i.e. were reduced to semiquinone radical species) only when NADH was used as substrate; succinate and ascorbate were without effect. Inhibitor experiments (rotenone, amytal, piericidin A) indicated that the anthracycline reduction site lies on the substrate side of ubiquinone. Doxorubicin and daunorubicin semiquinone radicals were readily detected by ESR spectroscopy. Doxorubicin and daunorubicin semiquinone radicals (g congruent to 2.004, signal width congruent to 4.5 G) reacted avidly with molecular oxygen, presumably to produce O2-, to complete the redox cycle. The identification of Complex I as the site of anthracycline reduction was confirmed by studies of ATP-energized reverse electron transport using succinate or ascorbate as substrates, in the presence of antimycin A or KCN respiratory blocks. Doxorubicin and daunorubicin inhibited the reduction of NAD+ to NADH during reverse electron transport. Furthermore, during reverse electron transport in the absence of added NAD+, doxorubicin and daunorubicin addition caused oxygen consumption due to reduction of molecular oxygen (to O2-) by the anthracycline semiquinone radicals. With succinate as electron source both thenoyltrifluoroacetone (an inhibitor of Complex II) and rotenone blocked oxygen consumption, but with ascorbate as electron source only rotenone was an effective inhibitor. NADH oxidation by doxorubicin during BH-SMP forward electron transport had a KM of 99 microM and a Vmax of 30 nmol X min-1 X mg-1 (at pH 7.4 and 23 degrees C); values for daunorubicin were 71 microM and 37 nmol X min-1 X mg-1. Oxygen consumption at pH 7.2 and 37 degrees C exhibited KM values of 65 microM for doxorubicin and 47 microM for daunorubicin, and Vmax values of 116 nmol X min-1 X mg-1 for doxorubicin and 114 nmol X min-1 X mg-1 for daunorubicin. In marked contrast with these results, 5-iminodaunodrubicin (a new anthracycline with diminished cardiotoxic potential) exhibited little or no tendency to undergo reduction, or to redox cycle with BH-SMP. Redox cycling of anthracyclines by mitochondrial NADH dehydrogenase is shown, in the accompanying paper (Doroshow, J. H., and Davies, K. J. A. (1986) J. Biol. Chem. 261, 3068-3074), to generate O2-, H2O2, and OH which may underlie the cardiotoxicity of these antitumor agents.
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PMID:Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase. 345 45


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